Hydroxy-methylmercaptobutyronitrile



Patented Feb. 20, 1951 HYDROXY-METll-IYLMERCAPTO- BUTYRONITRILE WilliamF. Gresham and Carl E. Schweitzer, Wilmington, Del., assignors to E. I.du Pont de Nemours & Company, Wilmington, DeL, a corporation of DelawareNo Drawing. Application August 1, 1949, Serial No. 108,063

1 Claim.

This invention relates to improvements in the synthesis of methionine,and to novel compositions of matter employed in the said synthesis. Moreparticularly this application relates to alpha-hydroxy-gammamethylmercaptobutyronitrile. The application is a continuation-inpart ofour copending application S. N. 624,328, filed October 24, 1945, now U.S. Patent 2,485,236, which in turn is a continuation-in-part of ourearlier application S. N. 522,966, filed February 18, 1944, nowabandoned.

The classical method for the synthesis of methionine is the methoddisclosed by Barger and Coyne (Biochem. J. 22, 1417- (1928)). Accordingto that well-known procedure, beta-methylmercapto-propionaldehyde issubjected to a Strecker synthesis, by means of which methionine isobtained in about 6% yield (cf. Organic Syntheses, volume XIV, page 60).

An object of the present invention is to provide novel compositions ofmatter which are especially adapted for use in the synthesis ofmethionine. Another object is to preparealpha-hydroxy-gamma-methylmercaptobutyronitrile as a novel compositionof matter. Other objects of this invention will appear hereinafter.

These and other objects are accomplished in accordance with thisinvention by means of a series of coacting and interdependent operationscomprising the following steps: (1) reaction between methyl mercaptanand acrolein to form beta-methylmercaptopropionaldehyde in the presenceof an alkaline or non-acidic (preferably an amine) catalyst; (2)addition of hydrogen cyanide to the resultantbeta-methylmercaptopropionaldehyde, preferably also in the presence ofan alkaline catalyst, such as pyridine, to form alpha-hydroxy-gammamethylmercaptobutyronitrile. Reaction ofalpha-hydroxy-gammamethylmercaptobutyronitrile with excess ammonia underhigh pressure produces alphaamino-gamma-methylmercaptobutyronitrile andhydroylsis of the said alpha-amino-gammamethylmercaptobutyronitrileproduces methionine. Equations illustrating the reactions may be writtenas follows:

In accordance with this invention, this synthesis of methionine isaccomplished in overall yields of about 70%.

The first step in the synthesis, namely, the reaction between methylmercaptan and acrolein,

'is best performed at a temperature of about 0 to 20 C., in the presenceof 0.05 to 5.0%, preferably 0.1 to 0.5%, of pyridine, based on theweight of the methyl mercaptan used. As the reaction proceeds, thetemperature may be allowed to increase somewhat, but it should not beallowed to rise above about 50 C., else excessive polymerization of theacrolein will occur. The methyl mercaptan preferably should be presentin excess of the amount theoretically required. In fact, about 2 mols ofmethyl mercaptan per mole of acrolein is usually desirable. One reasonfor this is to permit control of the reaction temperature, since theexothermic heat of the reaction can be dissipated conveniently as heatof vaporization of methyl mercaptan. Accordingly, the reaction vessel isgenerally equipped with a reflux condenser operated at a temperature of0 C. or lower for return of vaporized mercaptan to the reaction. Ifdesired the heat may be withdrawn by external cooling. In carrying outthe reaction between acrolein and methyl mercaptan, care must beexercised to prevent excessive polymerization of the acrolein before ithas had a chance to react with the mercaptan. This is achieved byinhibiting the acrolein with about 0.1 of hydroquinone, and by veryeflicient stirring of the mercaptan while adding the acrolein thereto.It is important that the acrolein be introduced directly into themercaptan and not, for example, along the inner walls of the reactionvessel, where polymerization of the acrolein may occur because of thealkaline catalyst present. Towards the end of the reaction, whichusually requires from 10 to 36 minutes, the temperature is preferablyallowed to reach about 20 C. After the reaction is complete, the excessmethyl mercaptan may be stripped off, and, if desired, the residue maybe distilled to yield as the almost exclusive product,beta-methylmercaptopropionaldehyde. This novel procedure givesbeta-methylmercaptopropionaldehyde in very high yield (98%).

The next step in the process of this invention is the preparation of thecyanohydrin of betamethylmercaptopriopionaldehyde, namely, alphahydroxygamma methylmercaptobutyronitrile, while is prepared also by the use ofpyridine as the preferred catalyst. Consequently, the betapreceding stepneed not necessarily be distilled or otherwise freed of pyridine, henceacrolein methyl mercaptan addition product, containing pyridine, may betreated directly with hydrogen cyanide. In the second step of thisinvention, hydrogen cyanide, preferably in about 10% exess, based uponthe beta-methyl-mercaptopropionaldehyde is added to the reaction productof the first step at a temperature in the range of about 15 to 75 C.(preferably 35 to 55 C.) with 0.1 to 0.5% of an amine catalyst, such aspyridine. The formation of the oyanhydrin takes place very easily, yieldafter about 30 minutes reaction time being practically quantitative.

In a specific embodiment, this hydroxynitrile, namelyalpha-hydroxy-gamn1a-methylmercaptobutyronitrile, may be isolated inpure form, and thereafter aminated as hereinafter set forth. Thisalpha-hydroxy gamma methylmercaptobutyronitrile is a novel compositionof matter which is particularly useful in, and especially adapted for,the herein described process for maldng methionine. Prior investigatorsin this field have never succeeded in isolating this ma- .terial, oreven obtaining it in crude or transitory form, and, consequently, theseprior processes for making methionine frombeta-methylmercaptopropionaldehyde without obtaining this intermediatehave invariably given low yields.

The hydroxynitrile mentioned above has outstanding utility as a.methionine precursor or intermediate. The conversion of thehydroxynitrile to methionine is accomplished by a series of steps, thefirst of which is to subject it to the action of ammonia. it is notnecessary to sepa rate the pyridine or other amine catalyst from theproduct of the preceding step prior to carrying on this amination, butsuch separation may beeilected if desired. The reaction of alphahydroxygamma methylmercaptobutyronitrile with ammonia is preferablyaccomplished by processing alpha-hydroxygamma-methylmercaptobutyronitrile at a temperature in the range of 10 to150 (3., preferably 75 to 90 0., with a large excess of ammonia (atleast 5 moles of ammonia per mole of cyanhydrin, preferably to 30moies), at a superatmospheric pressure of 5 to 1000 atmospheres,preferably about 10 to 100 atmospheres. At about room temperature thereaction may require up to 12 to 15 hours or more for completion, but at80 to 90 C., the reaction is complete in 15 to minutes. The yield ofalpha-amino-gamma methylnercaptobutyronitrile (i. e., methioninenitrile) under these conditions is virtually quantitative.

This amincnitrile (i. e., methionine nitrile) is disclosed in ourearlier applications S. N. 522,966 and S. N. 624,328. Prior attempts toobtain either this aminonitrile or the hydrochloride thereof haveinvariably met with failure. For example, Barger and Coyne (loc. cit.,pages 1420-1) reported that attempts to obtain the hydrochloride of thisaminonitrile have not been successful. The success of the presentmethionine synthesis is due, in large measure, to the fact that thehydroxynitrile, and the aminonitrile, are both obtained in isolableform. The pure aminonitrile, which is described in detail below, is athermally unstable compound, which cannot be distilled under ordinaryconditions, i. e. at pressures above a few millimeters. It can behydrolyzed, however, to give methionine in good yields. Specific methodsfor the hydrolysis of this nitrile are set forth in U. S. Patents2,432,478, 2,443,391 and 2,432,429. The successful preparation of theaminonitrile is probably due to the fact that the cyanhydrin is firstobtainable, as stated above, in isolable form, and is thereafter treatedwith high pressure ammonia. Ordinary ammoniation does not give asatisfactory result. In fact, unless very large excess, or highpressure, of ammonia is used, preferabiy above about 30 atmospheres, aprod not containing appreciable amounts of the unreacted cyanhydrin isobtained. The purest amino-nitrile is thus prepared at high ammoniationpressures. This is important since the separation of the aminonitrilefrom the cyanhydrin by physical methods is quite difficult or virtuallyimpossible. This is due in part to the thermal instability of theaminonitrile.

Because of the almost quantitative yield in the amination step, thehydrolysis of alpha-aminogamma-methylmercaptobutyronitrile to methioninemay be effected without intermediate steps or processing of materials.In continuous operation, the product of the preceding step is pumpedthrough a reaction vessel along with hot aqueous acid, such as sulfuricacid of about 10 to- 70% concentration, preferably about 50%. Thisproduces an aqueous solution of methionine nitrile sulfate. A preferredprocedure is to mix the alpha-amino-gamma-methy1mercaptobutyronitrilewith 50% sulfuric acid, and to heat the resulting methionine nitrilesulfate solution at a temperature close to the boiling point for aboutan hour or longer. Thereafter the mixture is cooled to about roomtemperature, and the sulfuric acid is neutralized with ammonia. Incertain instances the product at this stage has a rather dark color,which can be removed by means of decolorizing charcoal. To isolatemethionine from the resultant solution, any of the conventionaltechniques for separating a solute from a solvent may be employed. Thewater may be removed at low pressure, and the methionine can beextracted from the ammonium sulfate in the resulting residue by asuitable solvent. Alternatively, the solvent may be evaporated and theproduct isolated by fractional crystallization. The yield in thehydrolysis step generally is within the range of '70 to 75%, calculatedon the basis of the pure recrystallized product.

Example 1.Into a 200 cubic centimeter 3-necked flask equipped with astirrer, a Dry-Ice reflux condenser, a thermometer and a dropping funnelis placed a mixture of 96' grams of methyl mercaptan and 0.3 gram ofpyridine. With rapid stirring, acrolein (56 grams) containing 0.1%hydroquinone is introduced dropwise through the dropping funnel, initialtemperature being 5 C. As the reaction proceeds it is necessary toabsorb part of the reaction heat by surrounding the reaction vessel withan ice water bath. The reaction continues for about one hour, duringwhich time the reaction mixture is allowed to Warm up to 20 C. Theunreacting mercaptan (52 grams) and acrolein (3.6 grams) are recoveredby distillation at low pressure, the receiver being a cold trap at C.There remains a residue which distills quite completely at 60 0., 12 mm,which is the boiling point of beta-methylmercaptopropionaldehyde (Weightof beta-methylmercaptopropionaldehyde, 96 grams). This aidehyde isreturned to the reaction vessel and a little pyridine (0.3 gram) isadded. Into the mixture is introduced 27.2 grams of liquid hydrogencyanide. By suitable cooling, the tempera-' ture of the mixture ismaintained at 40 to 45 C. for about 20 minutes. The formation of thecyanhydrin takes place quite smoothly. When the reaction is complete theexcess hydrogen cyanide is removed by low pressure distillation into acold trap. There remains 118 grams of the cyanhydrin, i. e.alphahydroxy-gamma-methylmercaptobutyronitrile.

If it is desired to convert the oyanhydrin to methionine, the productthus obtained is transferred to a pressure resistant silver-lined vesselof about 900 c. c. capacity, and ammonia 00 grams) is injected. Thevessel is then agitated and heated to a temperature of 80 to 90 C., thecontents being under an autogenously developed pressure of aboutatmospheres. After 15 minutes at this temperature the reaction mixtureis cooled, and then withdrawn from the reaction vessel. Upon evaporationof the ammonia there remains a residue which is a mixture of water andalpha-amino-gamma-methylmercaptobutyronitrile. An aliquot portion ofthis residue is placed in a distilling flask and water is removedtherefrom by evaporation at low pressure. The remaining residue, whichis alpha-amino-gammamethylmercaptobutyronitrile, is obtained in quantitycorresponding to nearly quantitative yield. This residue is thereafteradded to the main portion of the aqueous aminonitrile. Withoutseparating the water from this amino nitrile, the mixture is addeddropwise to a solution containing 180 grams of concentrated sulfuricacid and 180 grams of water. The resulting mixture, which is an aqueoussolution of the sulfuric acid salt of methionine nitrile, is boiled for1.5 hours. Thereafter, it is cooled to room temperature, and neutralizedwith aqueous ammonium hydroxide. The solution thus obtained isdecolorized by boiling with a few grams of decolorizing charcoal. Afterremoval of the charcoal by filtration, the solution is placed in anevaporator, and water is removed at diminished pressure until thereremains a solid mixture of methionine and ammoninm sulfate. By repeatedextraction with liquid ammonia, the methionine is removed from theammonium sulfate. The methionine is isolated by evaporation of ammoniafrom this extract. There is obtained crude methionine which onrecrystallization from Water yields 112 grams of pure methionine,melting at 283 C.

Example 2.--To 75.5 grams (0.725 mole) of freshly distilledgamma-methylmercaptopropionaldehyde (B. P. 51 C./7 mm.) containing 0.5cc.

of pyridine catalyst there was added, with stirring and cooling toprevent a temperature in excess of C., 40 cc. (1.04 mole) of liquid HCN;this addition required 15 minutes and the mixture was allowed to reactfor an additional 15 minutes. The product was then placed on a vacuumpump and volatiles were removed, the final temperature and pressurebeing 40 C. at 2 mm. (product weight=84.8 grams). This product wasfurther purified by dissolving it in ether, extracting the ethersolution with water, and removing voltaile components from the etherlayer by means of a stream of CO2 (40 C./2 mm.) The resulting purifiedalpha-hydroxy-methylmercaptobutyronitrile was a virtually colorless thinliquid, which could not be satisfactorily distilled at ordinarypressures without decomposition. It had a density of about 1.129 at 25C., and an index of refraction of 1.4918 at 295 C. On standing, thismaterial tended to develop color, hence it was desirable to store it atrela-- tively low temperatures, suitably about -?-10 C. or lower. Thepurified product analyzed as follows: free HCN, 0.0%; total N, 10.38,10.45% (theory, 10.7%) total S, 23.8% (theory, 24.4%). These analysesidentify the material asalphahydroxy-gamma-methyl-mercaptobutyronitrile.

It will be understood that the present invention is not limited to theparticular embodiments which are hereinbefore used as illustrations. Forexample, it is not essential that the same catalyst, pyridine, beemployed in the first two steps in the synthesis of methionine, althoughgenerally there is an advantage in doing so. If desired, othernon-acidic catalysts may be employed for the reaction between acroleinand methyl mercaptan. Thus, charcoal, amines (piperidine, quinoline,methionine nitrile, triethanolamine,. etc.) lime, alkali metalalcoholates and the like: are operative as catalysts in the first step.If desired, the product obtained in step (2), (alpha-- hydroxy-gammamethylmercaptobutyronitrile) may be neutralized or acidified prior tothe amination, because its storage properties are better in the absenceof alkali. Other acids besides sulfuric acid may be employed in thehydrolysis of the aminonitrile to methionine, although comparativelypoor results are obtained with hydrochloric acid. For example, whencqui-molal quantities of the aminonitrile and 37% hydrochloric acid areheated at refluxing temperature for one hour, or allowed to standovernight at room temperature, a poor conversion (less than 20%) tomethionine is obtained. So far as methionine synthesis is concerned, theimproved results reported herein are due in part to the formation ofmethionine nitrile sulfate prior to hydrolysis.

Since many different embodiments of this invention may be made withoutdeparting from the spirit and scope thereof, it will be understood thatwe do not limit ourselves except as set forth in the appended claim.

We claim:

Alpha hydroxy gamma methyl-mercaptobutyronitrile.

WILLIAM F. GRESHAM. CARL E. BCHWEITZER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Gresham et al Oct. 18, 1949 OTHERREFERENCES Number

